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1.
Dermatitis ; 30(2): 116-128, 2019.
Article in English | MEDLINE | ID: mdl-30829810

ABSTRACT

BACKGROUND: An essential step in ensuring the toxicological safety of cosmetic or personal care products is the evaluation of the skin sensitizing potential of product ingredients. OBJECTIVE: We used a standardized protocol from cosmetic trade industry and consumer safety groups to evaluate the sensitization potential of ingredients in 3 commercially available cleansing conditioners. METHODS: A total of 33 ingredients were evaluated. Each ingredient underwent (1) dermatological evaluation, (2) in silico analysis for irritation and sensitization potential, and (3) a literature evaluation to determine risk of sensitization. Consumer exposure level was compared with the weight-of-evidence no-expected sensitization induction level for the constituent. If a no-expected sensitization induction level for a specific ingredient was not available, the dermal sensitization threshold approach was used. A margin of safety was calculated for each constituent. RESULTS: The margins of safety for all evaluated ingredients in the cleansing conditioners were greater than 1. CONCLUSIONS: This analysis indicates that exposure to the individual ingredients present in these cleansing conditioners would not be expected to induce dermal sensitization in a consumer under the examined exposure scenario.


Subject(s)
Dermatitis, Allergic Contact/etiology , Hair Preparations/adverse effects , Scalp Dermatoses/chemically induced , Skin Care/adverse effects , Adult , Clinical Protocols , Computer Simulation , Consumer Product Safety/standards , Female , Hair Preparations/toxicity , Humans , Risk Assessment , Scalp Dermatoses/etiology , Skin Care/methods
2.
Cutan Ocul Toxicol ; 38(1): 44-47, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30124079

ABSTRACT

Purpose/Aim: The U.S. Food and Drug Administration (FDA) does not require specific testing to demonstrate the safety of personal care and cosmetic products or their ingredients. Recently, there have been reports of skin irritation associated with the use of commercially available cleansing conditioners. The goal of this study was to implement a tier-based safety assessment to evaluate the skin irritation potential of six commercially available cleansing conditioners and their ingredients. MATERIALS AND METHODS: The first tier of testing utilized the Organization for Economic Co-operation and Development (OECD) QSAR Toolbox to perform an in silico evaluation of the skin irritation potential of the product ingredients, and the second tier of testing utilized an OECD in vitro guideline test to evaluate the skin irritation potential of each product. RESULTS: Thirty-two ingredients were evaluated using the OECD QSAR Toolbox profiler for the tier one analysis; nine ingredients received a structural alert for skin irritation/corrosion. In the tier two in vitro analysis, the evaluated cleansing conditioner products were all classified as non-irritants. CONCLUSIONS: These results provide evidence that use of the evaluated commercially available cleansing conditioners would not be expected to cause skin irritation among consumers. Additionally, this study demonstrates that the presence of structural alerts does not always accurately predict the safety of a product, as focused tier-based testing is necessary to comprehensively evaluate a product. This study illustrates a tier-based safety assessment approach, applicable to a wide variety of health endpoints, which efficiently and adequately evaluates the safety of personal care and cosmetic products and their ingredients.


Subject(s)
Hair Preparations/toxicity , Computer Simulation , Consumer Product Safety , Hair Preparations/chemistry , Hair Preparations/classification , Humans , Quantitative Structure-Activity Relationship , Risk Assessment , Skin/drug effects , Skin Irritancy Tests
3.
Dermatitis ; 29(6): 324-331, 2018.
Article in English | MEDLINE | ID: mdl-30422886

ABSTRACT

BACKGROUND: Many chemicals used for fragrance purposes in a diversity of products have allergenic potential. Based on such concerns, industry groups developed concentration limits for use of fragrance chemicals in personal care and cosmetic products. OBJECTIVE: The aim of this study was to use a quantitative risk assessment to evaluate the potential for skin sensitization induction resulting from daily exposure to fragrance chemicals present in personal care and cosmetic products. METHODS: Product-specific dermal consumer exposure levels were calculated based on product use data in US adult females and benchmarked against acceptable exposure levels based on reported no expected sensitization induction levels to determine a margin of safety for each fragrance under evaluation. CONCLUSIONS: The results demonstrate an increased risk of skin sensitization induction for several leave-on products (lipstick, solid antiperspirant, eye shadow, face cream) for most of the evaluated fragrance chemicals, particularly under high-use exposure scenarios. In contrast, rinse-off products (shampoo, conditioner, facial cleanser) were not associated with risk of skin sensitization induction. Because the approach was based on maximum use limits for fragrance chemicals with skin sensitization concerns, the results suggest these limits may not be protective, particularly in the United States.


Subject(s)
Cosmetics/adverse effects , Dermatitis, Allergic Contact/etiology , Perfume/adverse effects , Antiperspirants/adverse effects , Body Surface Area , Consumer Product Safety , Cosmetics/administration & dosage , Female , Hair Preparations/administration & dosage , Hair Preparations/adverse effects , Humans , Mathematical Concepts , Perfume/administration & dosage , Risk Assessment , Skin/drug effects , Skin Cream/administration & dosage , Skin Cream/adverse effects
4.
Dermatitis ; 29(3): 132-138, 2018.
Article in English | MEDLINE | ID: mdl-29570489

ABSTRACT

BACKGROUND: Kathon CG is a commonly used cosmetic-grade preservative that contains active ingredients methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI). OBJECTIVE: The aim of the study was to perform a skin sensitization induction risk assessment of daily exposure to Kathon CG after use of various personal care and cosmetic products. METHODS: We calculated an estimated daily consumer exposure level for rinse-off and leave-on products using the amount of product applied per application, number of applications per day, a retention factor, the MCI/MI concentration, and body surface area values. We assumed that the products contained the maximum recommended safe concentration of MCI/MI: 15 ppm in rinse-off products and 7.5 ppm in leave-on products. We compared estimated consumer exposure levels with the no expected sensitization induction level for MCI/MI and applied sensitization assessment factors to calculate product-specific margins of safety (MOSs). CONCLUSIONS: The MOSs for rinse-off products ranged from 5 to 63, whereas the MOSs for leave-on products ranged from 0.03 to 1.49. Overall, our results provide evidence that some leave-on products containing the maximum recommended safe concentration of Kathon CG may increase the risk of sensitization induction due to exposure to MCI/MI. In contrast, rinse-off products were not associated with a potential increased risk of skin sensitization induction.


Subject(s)
Dermatitis, Allergic Contact/diagnosis , Preservatives, Pharmaceutical/adverse effects , Thiazoles/adverse effects , Cosmetics/adverse effects , Cosmetics/analysis , Cosmetics/pharmacology , Dermatitis, Allergic Contact/etiology , Female , Humans , Preservatives, Pharmaceutical/analysis , Preservatives, Pharmaceutical/pharmacology , Risk Assessment , Skin/drug effects , Thiazoles/analysis , Thiazoles/pharmacology
5.
Crit Rev Toxicol ; 48(10): 853-901, 2018 11.
Article in English | MEDLINE | ID: mdl-30912993

ABSTRACT

Hip implants have improved the mobility and quality of life in millions of individuals. This review presents the evolution of scientific knowledge regarding the history and understanding of systemic and local metal toxicological concerns of hip implants designs utilizing metal-on-metal (MoM) bearing surfaces used in hip resurfacing arthroplasty (HRA) and total hip arthroplasty (THA). This analysis addresses: (1) the history of the development of MoM hip implants; (2) the clinical and toxicological rationale for introducing second-generation MoM implants in the early 2000s as an alternative to metal-on-polyethylene bearings; (3) the subsequent history regarding success and failure of second-generation MoM devices; (4) a detailed review of the history of MoM toxicology, including carcinogenic potential, metal blood levels, hypersensitivity, and release of wear particles; and (5) a review of local tissue effects and MoM patient management. We have included an analysis of MoM THA and HRA survivorship trends aggregated from over 200 studies. By around 2008, HRA continued to be a challenging procedure with variable success rates, and concurrently, some THA devices began to experience higher than expected revision rates based on annual registry reports. The unexpected THA outcomes and continued challenges with HRA devices prompted many surgeons to question the role of toxicological effects in device performance. Regarding hypersensitivity, while conversion to metal sensitized status in some MoM patients occurs based on the skin patch or lymphocyte transformation testing, there is no evidence of a causal relationship between positive test results and device failure. The weight of evidence indicates that nanoparticles released from MoM implants are cleared from the local synovial space under normal wear conditions. The available data indicate that there are no discernible increases in local or systemic tumors following CoCr alloy implantation. Systemic health effects are rarely reported in MoM implant patients and are unlikely when blood concentrations are below 300 µg/L except when patients have specific risk factors. Over time, patient management evolved to include assays aimed at predicting implant function (blood monitoring) and soft tissue reactions (MRI and ultrasound imaging). Validation of these biomarkers as a diagnostic tool for implant function, patient pain, and, ultimately, implant survival, remains lacking. After the introduction of these biomarkers, differences in implant revision decisions emerged based on imaging abnormalities, increased serum metal ion levels, and overall clinical presentation. Discrepancies in patient management algorithms and the lack of consensus in local biological effects terminology have contributed to variability in reporting incidence, etiology, and dose effects on local tissue responses in MoM implants. This variability has contributed to a debate regarding the benefit or risk of revising asymptomatic patients. Therefore, while toxicological assessments of normal functioning MoM implants indicate that MoM implants are relatively safe because of low wear and clearance of metal, more analysis of revision data is needed in order to best inform patient management decisions, particularly for asymptomatic patients, as well as patients with minor symptoms under consideration for conservative pain management treatments.


Subject(s)
Hip Prosthesis/adverse effects , Metal-on-Metal Joint Prostheses/adverse effects , Metals/toxicity , Prosthesis Design , Prosthesis Failure , Arthroplasty, Replacement, Hip , Humans , Metals/blood , Risk Factors , Surface Properties
6.
Psychol Crime Law ; 24(9): 915-934, 2018.
Article in English | MEDLINE | ID: mdl-30745792

ABSTRACT

In the American criminal justice system the vast majority of criminal convictions occur as the result of guilty pleas, often made as a result of plea bargains, rather than jury trials. The incentives offered in exchange for guilty pleas mean that both innocent and guilty defendants plead guilty. We investigate the role of attorneys in this context, through interviews with criminal defense attorneys. We examine defense attorney perspectives on the extent to which innocent defendants are (and should be) pleading guilty in the current legal framework and their views of their own role in this complex system. We also use a hypothetical case to probe the ways in which defense attorneys consider guilt or innocence when providing advice on pleas. Results indicate that attorney advice is influenced by guilt or innocence, but also that attorneys are limited in the extent to which they can negotiate justice for their clients in a system in which uncertainty and large discrepancies between outcomes of guilty pleas and conviction at trial can make it a sensible option to plead guilty even when innocent. Results also suggest conflicting opinions over the role of the attorney in the plea-bargaining process.

7.
Arch Environ Occup Health ; 73(5): 292-301, 2018.
Article in English | MEDLINE | ID: mdl-28692341

ABSTRACT

Approximately 10,000 gallons of crude 4-methylcyclohexanemethanol and propylene glycol phenyl ether were accidentally released into the Elk River upstream from a water treatment facility in West Virginia. The objective of this study was to use logistic and Poisson regression analyses to determine the effect potential exposures had on adverse birth outcomes (birth weight, small for gestational age, and abnormal Apgar score). We adjusted for confounding factors and assessed prevalence of adverse birth outcomes by residential location and timing of the pregnancy. There were no statistically significant interactions between residential location and timing of the pregnancy (range of p values: .157-.806). Changes in the prevalence of birth outcomes were consistent before and after the spill regardless of residential location. There was no evidence of an association between adverse birth outcomes and potential exposure to the released chemicals.


Subject(s)
Apgar Score , Birth Weight/drug effects , Cyclohexanes/analysis , Infant, Small for Gestational Age , Prenatal Exposure Delayed Effects/epidemiology , Water Pollutants, Chemical/analysis , Adult , Female , Humans , Infant, Newborn , Male , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prevalence , Residence Characteristics , Seasons , West Virginia/epidemiology , Young Adult
8.
Cutan Ocul Toxicol ; 36(4): 351-355, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28277879

ABSTRACT

Crude 4-methylcyclohexanemethanol (MCHM) is an industrial chemical used to wash and clean coal. On January 9th, 2014 approximately 10,000 gallons of a mixture containing crude MCHM were released into the Elk River near Charleston, West Virginia, contaminating the local water supply. Following the spill, residents reported numerous health complaints, and sought medical attention for ailments including rashes and itching. The relationship between the complaints and the spill were unknown, as such symptoms are reported frequently in the background. In this study, the primary irritation potential of crude MCHM was evaluated in 206 individuals who underwent 48 hour semi-occluded patch testing. MCHM concentrations assessed in this study were 1, 5, 15, and 100 ppm. No appreciable skin reactions were observed in individuals at any concentration. Three of the five concentrations evaluated were above the highest measured concentration of MCHM in the tap water of residents in West Virginia (3.7 ppm). The results of this study suggest that crude MCHM would not be a dermal irritant for the vast majority, if not all, potentially exposed persons at the concentrations in the water reported after the spill.


Subject(s)
Cyclohexanes/toxicity , Skin/drug effects , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Patch Tests , Young Adult
9.
Crit Rev Toxicol ; 45 Suppl 2: 1-55, 2015.
Article in English | MEDLINE | ID: mdl-26509789

ABSTRACT

Crude 4-methylcyclohexanemethanol (MCHM) is an industrial solvent used to clean coal. Approximately 10 000 gallons of a liquid mixture containing crude MCHM were accidently released into the Elk River in West Virginia in January 2014. Because of the proximity to a water treatment facility, the contaminated water was distributed to approximately 300 000 residents. In this review, experimental data and computational predictions for the toxicity for crude MCHM, distilled MCHM, its other components and its putative metabolites are presented. Crude MCHM, its other constituents and its metabolites have low to moderate acute and subchronic oral toxicity. Crude MCHM has been shown not to be a skin sensitizer below certain doses, indicating that at plausible human exposures it does not cause an allergic response. Crude MCHM and its constituents cause slight to moderate skin and eye irritation in rodents at high concentrations. These chemicals are not mutagenic and are not predicted to be carcinogenic. Several of the constituents were predicted through modeling to be possible developmental toxicants; however, 1,4-cyclohexanedimethanol, 1,4-cyclohexanedicarboxylic acid and dimethyl 1,4-cyclohexanedicarboxylate did not demonstrate developmental toxicity in rat studies. Following the spill, the Centers for Disease Control and Prevention recommended a short-term health advisory level of 1 ppm for drinking water that it determined was unlikely to be associated with adverse health effects. Crude MCHM has an odor threshold lower than 10 ppb, indicating that it could be detected at concentrations at least 100-fold less than this risk criterion. Collectively, the findings and predictions indicate that crude MCHM poses no apparent toxicological risk to humans at 1 ppm in household water.


Subject(s)
Chemical Hazard Release , Cyclohexanes/toxicity , Environmental Exposure/adverse effects , Toxicity Tests , Water Pollutants, Chemical/toxicity , Water Pollution, Chemical/adverse effects , Water Supply , Animals , Biotransformation , Computer Simulation , Cyclohexanes/pharmacokinetics , Dose-Response Relationship, Drug , Humans , Models, Theoretical , Risk Assessment , Risk Factors , Water Pollutants, Chemical/pharmacokinetics , Water Quality
10.
Photodermatol Photoimmunol Photomed ; 31(4): 212-23, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25771707

ABSTRACT

BACKGROUND/PURPOSE: Studies have shown that individuals apply less than the 2 mg/cm(2) lotion sunscreen needed to achieve the labeled SPF. However, there is little information regarding the application of spray and stick sunscreens. The objectives of this study were to measure the amount of sunscreen applied to skin by different application methods, to examine the relationship between application and demographic factors, and to evaluate the potential for sensitization from the preservative methylisothiazolinone (MI) in lotion sunscreens. METHODS: Fifty-two participants applied lotion, spray, and stick sunscreen and answered a questionnaire. Lotion sunscreens were tested for MI content, and a margin of safety for the induction of skin sensitization was calculated. RESULTS: The geometric means for the application thickness of lotion, spray, and stick sunscreens were 1.1, 1.6, and 0.35 mg/cm(2), respectively. Several factors influenced sunscreen application thickness, including age and skin type. The MI concentration in tested sunscreen lotions ranged from <1 to 5.6 ppm, and likely MI exposures were below the threshold for induction of allergy (margin of safety > 8.1). CONCLUSIONS: In this study, sunscreen users applied different amounts of sunscreen depending on the application method, affording different levels of sun protection. Typical use of the sunscreens is not likely to result in MI sensitization.


Subject(s)
Sunburn/prevention & control , Sunscreening Agents/administration & dosage , Thiazoles/administration & dosage , Administration, Topical , Adult , Female , Humans , Male
11.
J Toxicol Environ Health A ; 76(14): 883-93, 2013.
Article in English | MEDLINE | ID: mdl-24053365

ABSTRACT

Textiles are commonly treated with formaldehyde-based residues that may potentially induce allergic contact dermatitis in sensitive individuals. This study examined the initial formaldehyde content in clothing and resulting changes due to care activities. Twenty clothing articles were examined and 17 of them did not have detectable levels of formaldehyde. One shirt contained a formaldehyde concentration of 3172 ppm, and two pairs of pants had formaldehyde concentrations of 1391 ppm and 86 ppm. The two highest results represent formaldehyde levels that are up to 40-fold greater than international textile regulations. The two items with the greatest formaldehyde content were washed and dried in a manner similar to that used by consumers, including hand and machine washing in hot or cold water followed by air or machine drying. The washing and drying procedures reduced formaldehyde levels to between 26 and 72% of untreated controls. Differences in the temperature or type of washing and drying did not result in a clear trend in the subsequent formaldehyde content. In addition, samples were hot ironed, which did not affect the formaldehyde content as significantly. Understanding the formaldehyde content in clothing and its potential reduction through care activities may be useful for manufacturers and formaldehyde-sensitive individuals.


Subject(s)
Clothing , Formaldehyde/analysis , Laundering , Textiles/analysis , Dermatitis, Allergic Contact/etiology , Formaldehyde/adverse effects , Humans
12.
Food Chem Toxicol ; 56: 60-6, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23429043

ABSTRACT

1,2-Benzisothiazolin-3-one (BIT; CAS # 2634-33-5) is a preservative used in consumer products. Dermal exposure to BIT at sufficient dose and duration can produce skin sensitization and allergic contact dermatitis in animals and susceptible humans.The purpose of this study is to derive a maximal concentration of BIT in various consumer products that would result in exposures below the No Expected Sensitization Induction Level (NESIL), a dose below which skin sensitization should not occur. A screening level exposure estimate was performed for several product use scenarios with sunscreen, laundry detergent, dish soap, and spray cleaner. We calculated that BIT concentrations below the following concentrations of 0.0075%, 0.035%, 0.035%, 0.021% in sunscreen, laundry detergent, dish soap, and spray cleaner, respectively, are unlikely to induce skin sensitization. We completed a pilot study consisting of bulk sample analysis of one representative product from each category labelled as containing BIT, and found BIT concentrations of 0.0009% and 0.0027% for sunscreen and dish soap, respectively. BIT was not detected in the laundry detergent and spray cleaner products above the limit of detection of 0.0006%. Based on publically available data for product formulations and our results, we were able to establish that cleaning products and sunscreens likely contain BIT at concentrations similar to or less than our calculated maximal safe concentrations and that exposures are unlikely to induce skin sensitization in most users.


Subject(s)
Consumer Product Safety , Preservatives, Pharmaceutical/toxicity , Sunscreening Agents/analysis , Thiazoles/toxicity , Animals , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/etiology , Detergents/analysis , Detergents/toxicity , Dose-Response Relationship, Drug , Humans , Pilot Projects , Preservatives, Pharmaceutical/analysis , Risk Assessment , Soaps/analysis , Soaps/toxicity , Thiazoles/analysis
13.
Ann Occup Hyg ; 57(6): 705-16, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23316079

ABSTRACT

Benzene is an aromatic hydrocarbon that, with sufficient cumulative lifetime doses, can cause acute myelogenous leukemia. Because of its volatility and solvent properties, it was used in the printing industry in inks, ink solvents, and cleaning agents from the 1930s to the 1970s. This analysis represents the first known attempt to gather and synthesize the available data on historical airborne benzene concentrations in printing facilities and exposures to pressmen. The sources of fugitive benzene vapors from printing operations have been identified as evaporation from ink fountains, exposed sections of the printing cylinder, the paper web, the paper post exit, and spilled ink. In addition, specific activities that could lead to benzene exposure, such as filling the fountains, using solvents to clean the press, and using solvents as personal cleaning agents, potentially occurred multiple times per work period. Eighteen studies were identified that reported workplace airborne concentrations in printing facilities between 1938 and 2006. Typical benzene air concentrations, considering both personal and area samples of various durations, were as high as 200 p.p.m. in the 1930s through the 1950s, 3-35 p.p.m. in the 1960s, 1.3-16 p.p.m. in the 1970s, 0.013-1 in the 1980s, and far less than 1 p.p.m. in the 1990s and 2000s. The decrease in benzene air concentrations by the late 1970s was likely to be linked to the decreased benzene content of printing materials, increased engineering controls, and to more stringent occupational exposure limits.


Subject(s)
Air Pollutants, Occupational/analysis , Benzene/adverse effects , Benzene/analysis , Printing/history , Air Pollution, Indoor/analysis , Environmental Monitoring , History, 20th Century , History, 21st Century , Humans , Inhalation Exposure/analysis , Ink , Occupational Exposure/analysis , Occupational Health/history , Occupational Health/standards , Printing/instrumentation , Printing/methods , Solvents/analysis
14.
Biochem Pharmacol ; 79(9): 1345-51, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20036217

ABSTRACT

Flavin-containing monooxygenase (FMO) expression in male mouse liver is altered after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or castration. Because TCDD is slowly eliminated from the body, we examined hepatic Fmo mRNA alterations for up to 32 days following 10 or 64 microg/kg TCDD exposure by oral gavage in male C57BL/6J mice. Fmo2 mRNA was significantly induced at 1, 4, and 8 days whereas Fmo3 mRNA was also induced at 32 days relative to controls. Fmo3 mRNA levels exhibited a dose-dependent increase at 4, 8, and 32 days after exposure; Fmo1, Fmo4, and Fmo5 mRNA did not exhibit clear trends. Because castration alone also increased Fmo2, Fmo3, and Fmo4 mRNA we examined the combined effects of castration and TCDD treatment on FMO expression. A greater than additive effect was observed with Fmo2 and Fmo3 mRNA expression. Fmo2 mRNA exhibited a 3-5-fold increase after castration or 10 microg/kg TCDD exposure by oral gavage, whereas an approximately 20-fold increase was observed between the sham-castrated control and castrated TCDD-treated mice. Similarly, treatment with 10 microg/kg TCDD alone increased Fmo3 mRNA 130- and 180-fold in the sham-castrated and castrated mice compared to their controls respectively, whereas, Fmo3 mRNA increased approximately 1900-fold between the sham control and castrated TCDD-treated mice. An increase in hepatic Fmo3 protein in TCDD-treated mice was observed by immunoblotting and assaying methionine S-oxidase activity. Collectively, these results provide evidence for isoform distinct time-, dose-, and castration-dependent effects of TCDD on FMO expression and suggest cross-talk between TCDD and testosterone signal transduction pathways.


Subject(s)
Liver/drug effects , Liver/enzymology , Orchiectomy , Oxygenases/metabolism , Polychlorinated Dibenzodioxins/toxicity , Animals , Gene Expression Regulation, Enzymologic/physiology , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Mice , Oxygenases/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
15.
J Pharmacol Exp Ther ; 329(3): 1148-55, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19307449

ABSTRACT

Flavin-containing monooxygenases (FMOs) play significant roles in the metabolism of drugs and endogenous or foreign compounds. In this study, the regional distribution of FMO isoforms 1, 3, and 4 was investigated in male Sprague-Dawley rat liver and kidney using immunohistochemistry (IHC). Rabbit polyclonal antibodies to rat FMO1 and FMO4, developed using anti-peptide technology, and commercial anti-human FMO3 antibody were used; specificities of the antibodies were verified using Western blotting, immunoprecipitation, and IHC. In liver, the highest immunoreactivity for FMO1 and FMO3 was detected in the perivenous region, and immunoreactivity decreased in intensity toward the periportal region. In contrast, FMO4 immunoreactivity was detected with the opposite lobular distribution. In the kidney, the highest immunoreactivity for FMO1, -3, and -4 was detected in the distal tubules. FMO1 and FMO4 immunoreactivity was also detected in the proximal tubules with strong staining in the brush borders, whereas less FMO3 immunoreactivity was detected in the proximal tubules. Immunoreactivity for FMO3 and FMO4 was detected in the collecting tubules in the renal medulla and the glomerulus, whereas little FMO1 immunoreactivity was detected in these regions. The FMO1 antibody did not react with human liver or kidney microsomes. However, the FMO4 antibody reacted with male and female mouse and human tissues. These data provided a compelling visual demonstration of the isoform-specific localization patterns of FMO1, -3, and -4 in the rat liver and kidney and the first evidence for expression of FMO4 at the protein level in mouse and human liver and kidney microsomes.


Subject(s)
Kidney/metabolism , Liver/metabolism , Oxygenases/metabolism , Protein Isoforms/metabolism , Animals , Antibodies/immunology , Antibody Specificity/immunology , Cross Reactions/immunology , Female , Golgi Apparatus/metabolism , Humans , Kidney Cortex/metabolism , Kidney Glomerulus/metabolism , Kidney Medulla/metabolism , Kidney Tubules/metabolism , Male , Mice , Mice, Inbred Strains , Microsomes/metabolism , Oxygenases/immunology , Protein Isoforms/immunology , Rats , Rats, Sprague-Dawley
16.
Drug Metab Dispos ; 36(12): 2468-74, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18775983

ABSTRACT

Rats are a common animal model for metabolism and toxicity studies. Previously, the enzymatic properties of rat flavin-containing monooxygenase (FMO) 1 purified from hepatic and renal microsomes and that of FMO3 purified from hepatic microsomes were characterized. This study investigated the physical, immunological, and enzymatic properties of FMO3 purified from male rat kidney microsomes and compared the results with those obtained with isolated rat liver FMO3. Renal FMO3 was purified via affinity columns based on the elution of L-methionine (Met) S-oxidase activity and reactivity of the eluted proteins with human FMO3 antibody. In general, Met S-oxidase-specific activity was increased 100-fold through the purification steps. The resulting protein had similar mobility (approximately 56 kDa) as isolated rat liver FMO3 and cDNA-expressed human FMO3 by SDS-polyacrylamide gel electrophoresis. When the isolated kidney protein band was subjected to trypsin digestion and matrix-assisted laser desorption ionization/time of flight mass spectral analysis, 34% of the sequence of rat FMO3 was detected. The apparent K(m) and V(max) values for rat kidney FMO3 were determined using the known FMO substrates Met, seleno-L-methionine, S-allyl-L-cysteine (SAC), and methimazole (N-methyl-2-mercaptoimidazole). The stereoselectivity of the reactions with Met and SAC were also examined using high-performance liquid chromatography. The obtained kinetic and stereoselectivity results were similar to those we obtained in the present study, or those previously reported, for rat liver FMO3. Taken together, the results demonstrate many similar properties between rat hepatic and renal FMO3 forms and suggest that renal FMO3 may play an important role in kidney metabolism of xenobiotics containing sulfur and selenium atoms.


Subject(s)
Kidney/chemistry , Microsomes/chemistry , Oxygenases/chemistry , Oxygenases/isolation & purification , Amino Acid Sequence , Animals , Catalysis , Cysteine/analogs & derivatives , Cysteine/chemistry , Kinetics , Male , Methimazole/chemistry , Methionine/chemistry , Methionine/metabolism , Molecular Sequence Data , Molecular Weight , NADP/chemistry , Rats , Rats, Sprague-Dawley , Selenomethionine/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stereoisomerism
17.
Mol Ecol ; 12(11): 2885-93, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14629370

ABSTRACT

While microsatellites have been used to examine genetic structure in local populations of Neotropical trees, genetic studies based on such high-resolution markers have not been carried out for Mesoamerica as a whole. Here we assess the genetic structure of the Mesoamerican mahogany Swietenia macrophylla King (big-leaf mahogany), a Neotropical tree species recently listed as endangered in CITES which is commercially extinct through much of its native range. We used seven variable microsatellite loci to assess genetic diversity and population structure in eight naturally established mahogany populations from six Mesoamerican countries. Measures of genetic differentiation (FST and RST) indicated significant differences between most populations. Unrooted dendrograms based on genetic distances between populations provide evidence of strong phylogeographic structure in Mesoamerican mahogany. The two populations on the Pacific coasts of Costa Rica and Panama were genetically distant from all the others, and from one another. The remaining populations formed two clusters, one comprised of the northern populations of Mexico, Belize and Guatemala and the other containing the southern Atlantic populations of Nicaragua and Costa Rica. Significant correlation was found between geographical distance and all pairwise measures of genetic divergence, suggesting the importance of regional biogeography and isolation by distance in Mesoamerican mahogany. The results of this study demonstrate greater phylogeographic structure than has been found across Amazon basin S. macrophylla. Our findings suggest a relatively complex Mesoamerican biogeographic history and lead to the prediction that other Central American trees will show similar patterns of regional differentiation.


Subject(s)
Genetic Variation , Genetics, Population , Geography , Meliaceae/genetics , Central America , Cluster Analysis , Gene Frequency , Microsatellite Repeats/genetics , Models, Genetic
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